Inflammatory skin diseases encompass many pathologies such as rosacea, psoriasis, contact eczema, atopic dermatitis, or further pruritus.
Rosacea is a chronic and gradual common inflammatory dermatosis related to vascular disorders. It mainly affects the central portion of the face and is characterized by reddening of the face accompanied by hot flushes, facial erythema, papules, pustules, telangiectasia and sometimes ocular lesions called ocular rosacea. In extreme cases, in particular in humans, hypertrophy is observed at the nasal level called rhinophyma. Rosacea occurs between 25 and 70 years old and develops over several years with remission phases and exacerbation phases. Rosacea is much more common in persons with a pale complexion and particularly affects women. However, the most severe attacks are generally observed in men. Rosacea is classified in 4 sub-types depending on various clinical characteristics (Wilkin J et al., JAAD, 2002, 46: 584-587): erythematotelangiectatic rosacea (sub-type 1), papulo-pustular rosacea (sub-type 2), phymatous rosacea (sub-type 3) and ocular rosacea (sub-type 4). More rare forms of rosacea also exist such as the granulomatous variant which is characterized by papules or yellow, brown or red indurated nodules, and by monomorphic lesions at the papules.
The pathological signs of rosacea vary according to the sub-type of the disease. Nevertheless, it is noted that local inflammatory reactions and vascular hyperactivity are constant signs of rosacea.
The pathogenesis of rosacea is poorly known and may involve several factors. The disease may be caused or promoted by the presence of follicular microorganisms such as bacteria and mites Demodex Folliculorum, an aberrant innate immune response, an abnormal vascular reactivity and hypersensitivity to environmental stimuli such as exposure to UVs, sudden changes in temperature, consumption of hot drinks, spiced dishes and alcohol, strong emotions (stress, embarrassment, anger . . . ).
Conventionally, rosacea is treated orally or via a topical route with antibiotics such as tetracyclines, erythromycin, clindamycin, but also by vitamin A, salicylic acid, azelaic acid, sulfur sulfacetamide, metronidazole or by isotretinoin in severe forms. The available therapies may have unpleasant secondary effects for the patient such as irritations and their effectiveness may be limited towards certain symptoms or rosacea sub-type. Finally, these treatments generally aim the symptoms of the disease without treating the cause thereof.
Psoriasis is a chronic dermatosis, which evolves with eruptions or with fits, which affects about 2% of the population. Psoriasis is characterized by epidermal hyperproliferation (accelerated renewal of the epidermis) associated with keratinization disorders. Psoriasic lesions generally appear as erythemato-squamous plaques, often pruriginous plaques. Infiltration of leukocytes and moderate inflammation of the dermis and of the epidermis is generally observed at the lesions, which suggests that psoriasis would be a self-immune disease. Psoriasis frequently affects friction areas such as knees, elbows and the lumbar region as well as the scalp, the hands and the feet. Several forms of psoriasis are distinguished (guttate psoriasis, pustular psoriasis, . . . ), plaque psoriasis (or vulgar psoriasis) being the most common form. Etiology of psoriasis at the present time remains poorly known. One case out of two seems to be of family origin. Various predisposition genes have been discovered. Recent studies suggest that psoriasis also results from immune anomalies. Finally, psoriasis may be triggered or worsened by a certain number of factors such as psychological stress, overworking, alcohol, food diet, overweight, certain infections or the taking of drugs. Local treatments and phototherapy are used for moderate forms of psoriasis. Systemic treatments are reserved for severe forms of psoriasis. These treatments have variable effectiveness and may induce bothersome secondary effects.
Eczema groups pruriginous erythemato-vesicular inflammatory dermatoses. These pathologies generally develop in several phases: An erythematous phase, a vesicular phase, an exudation phase and a desquamation phase. Nummular eczema, contact eczema which is induced by an allergic reaction towards an exogenous agent, and atopic dermatitis are distinguished inter alia.
Atopic dermatitis (also called atopic dermatitis or atopic eczema) is a chronic dermatosis, evolving with eruptions and which essentially affects children, in particular newly born children. Atopic dermatitis is characterized by significant skin dryness (xerosis), by papular or vesicular, squamous erythematous inflammatory lesions with possibly cracks and lichenification of lesions. Atopic dermatitis affects the convexities of the cheeks, of the limbs and of the scalp in newly born children. In older children and in adults, the lesions are essentially located at the folds. Just like rosacea and psoriasis, pathogenesis of atopic dermatitis is poorly known. Genetic predisposition and/or an immune anomaly is often put forward. Certain factors may cause or worsen eruptions of atopic dermatitis: Food diet (egg, dairy product, peanut), stress, exposure to certain environmental pollutants or irritants (mites, pollens, water, limestone, perfumes, metals . . . ).
The treatment of atopic dermatitis is essentially symptomatic. It may comprise the local application of corticoids and of emollient. Anti-histaminics may be prescribed for relieving pruritus.
Finally, pruritus is a functional disorder which may be defined as a “sensation which causes the need to scratch oneself”. It may be localized or generalized. This is a frequent symptom, in particular of inflammatory dermatoses with skin lesions such as psoriasis and atopic dermatitis. Nevertheless, certain prurituses are not associated with specific skin lesions (pruritus “sine materia”). Pruritus may then be caused by a general affection, be of neurological or psychological origin or be associated with skin dryness (xerosis). The pruritus may be caused or worsened by hypersensitivity to external factors (chemicals, temperature and humidity variations, hard water . . . ). In certain cases, the pruritus is a neurological sign sustained and/or amplified by a local inflammatory reaction resulting from the scratching. There does not exit any general treatment of pruritus.
At the present time, therefore there still exists a need for new treatments against inflammatory skin diseases, in particular rosacea.
The voltage-dependent sodium channels are the essential actors for initiating and propagating action potentials at the so-called “excitable” cells. These sodium channels are mainly expressed at the neurones of the central and peripheral nervous system and at muscle cells. These are transmembrane proteins comprising a large alpha (α) sub-unit of about 260 kDa associated with one or several beta sub-units from 33 to 38 kDa. The alpha sub-unit forms the core of the channel and comprises four homologous membrane domains (I-IV), each consisting of 6 transmembrane segments (S1-S6). The membrane domains of the alpha sub-unit are connected together by large intracellular loops which comprise many regulation sites. The alpha sub-unit is responsible for the conductance and selectivity properties of the channel while the beta sub-units are involved in the stabilization and in the kinetic properties of the channel. To this day, 10 isoforms for the alpha sub-unit have been identified in humans. The name assigned to these isoforms contains the symbol of the transported ion (Na), with as an index the regulator element (the voltage v). The figures which follow designate the sub-family of genes and the number associated with the relevant isoform. To this day, the main sub-family of genes comprises the Nav 1.1 to Nav 1.9 isoforms. An additional isoform, further away. Nax has also been identified. The sequence identity percentage between the different isoforms Nav 1.1 to Nav 1.9 is of at least 45%. The isoforms Nav 1.1 to Nav 1.9 are inter alia differentiated by their sensitivity to tetrodotoxin (TTX), a very powerful and selective blocker of sodium channels, and by their tissue distribution. The isoforms Nav 1.1 to Nav 1.4, Nav 1.6 and Nav 1.7 are said to be sensitive to TTX with EC50s of the order of one nanomolar. The isoforms Nav 1.5, Nav 1.8 and Nav 1.9 are considered, as for them, as resistant to TTX. In this respect, the EC50 of the TTX for Nav 1.9 is of about 200 μM. As regards tissue distribution, the isoforms Nav 1.1, Nav 1.2, Nav 1.3 and Nav 1.6 are mainly expressed at the central nervous system. The isoform Nav 1.4 is mainly expressed at skeletal myocytes while Nav 1.5 is essentially present, in adult individuals, at the cardiac myocytes. Finally, the isoforms Nav 1.7, Nav 1.8 and Nav 1.9 are expressed at the peripheral nervous system (PNS). Nav 1.9 was mainly detected at the sensitive neurones of spinal ganglia where it would play a role in the perception of pain (nociception). Finally, Nax is expressed at the heart, the uterus, the smooth muscle, astrocytes and certain neurones of the hypothalamus and of the central nervous system. For a review relating to the voltage-dependent sodium channels, reference may be made to Yu and Caterall, Genome Biology, 2003, 4: 207 or Caterall et al., Pharmacological Reviews, 2005, 57:397-409.
To the knowledge of the Applicant, no link has been established in the state of the art between the expression of a Nav isoform, in particular Nav 1.9, and inflammatory skin diseases.